1989 Fiscal Year Annual Research Report

チトクロームPー450を中心とした薬物代謝酵素遺伝子発現と化学発癌

Research Project

Project/Area Number	01010005
Research Institution	Tohoku University
Principal Investigator	渡辺民朗東北大学, 抗酸菌病研究所, 教授 (40006101)
Co-Investigator(Kenkyū-buntansha)	山添康慶應義塾大学, 医学部, 講師 (00112699) 藤田正一千葉大学, 薬学部, 助教授 (10143314) 十川和博東北大学, 理学部, 助教授 (80175421) 佐藤清美弘前大学, 医学部, 教授 (50006079) 鎌滝哲也北海道大学, 薬学部, 教授 (00009177)
Keywords	チトクロームPー450遺伝子 / チトクロームPー450cDNA / チトクロームPー450蛋白 / 癌原性化学物質の代謝 / 遺伝子転写調節蛋白 / アセチルトランスフェラーゼ / グルタチオンSートランスフェラーゼ / ヒト遺伝子のRFLP
Research Abstract	1.P450、アセチルトランスフェラーゼ(AT)の遺伝子構造とその発現調節:メチルコラントレン(MC)で誘導されるハムスター肝P450MCI(IA2)(芳香族アミンなどの代謝)、MCII(IIA)(アフラトキシンの代謝)のcDNAの全塩基配列、ラット肝の培養により誘導されP450(Mー1)抗体と反応する新しいP450のcDNA塩基配列、癌原性アリルアミンの代謝に重要なATー1のcDNAの塩基配列を決定した。ラットP450IA1遺伝子の誘導的発現に関与する基本的転写因子(BTE)に結合する蛋白のcDNAを分離し、56KDaの分子量を決定した。ヒトP450humanー2のcDNAを酵母内で発現し、この蛋白はベンツピレンとメフェニトインの代謝活性が強いことを確かめる。P450IA1遺伝子に属するイヌとサルのcDNAを分離し、酵母内で発現すると、変異原の活性化能のテストでベンツピレンへの感受性はなかった。2.P450、グルタチオンSートランスフェラーゼ(GST)の蛋白の精製とその特質:P450II掛C遺伝子に属すが、アフラトキシンB_1の活性化に関与するイヌP450D1とラットP450maleと、活性化能の低いカニクイザルP450MKー1とヒトP450HMー2とに分かれ、P450IIIAに属するサルP450MKー2、ヒトP450HMー1も共に低かった。ジアルキルニトロサミンの活性化には、アルキル基の種類によりP450IIE1とP450IIC12への依存性が異なっている。発癌剤アリルメタノールの硫酸エステルを不活性化する新しいGSTを分離精製した。3.ヒト遺伝子多型性:P450IA1遺伝子でII型制限酵素Mspー1、P450IIE1遺伝子でMspー1、Rsaー1、Draー1、P450IIIA遺伝子でEcoRー1部位にRFLPが認められた。4.将来への展望:癌原性化学物質の代謝に関与する新たなP450遺伝子の同定を試み、ヒトでのRFLPと遺伝的素因との関連をみる。

Research Products

(39 results)

All Other

All Publications (39 results)

[Publications] Ohmachi,T.: "Purification and characterization of cytochrome P-450 from liver microsomes of 3-methylcholanthrene-treated crab-eating monkeys." J.Biochem.105. 307-311 (1989)
[Publications] Watanabe,M.: "Role of cytochrome P-450 in chemical toxicity and carcinogenesis." J.Toxicol.Pathol.2. 241-251 (1989)
[Publications] Kikuchi,H.: "Complementary DNA sequence of 3-methylcholanthrene-inducible P-450 from the rat lung." Tohoku J.Exp.Med.(1990)
[Publications] Komori,M.: "Molecular cloning and sequence analysis of cDNA containing the entire coding region for human fetal liver cytochrome P-450." J.Biochem.105. 161-163 (1989)
[Publications] Ohta,K.: "Purification of cytochrome P-450 from polychlorinated biphenyl-treated crab eating monkeys:High homology to a form of human cytochrome P-450." Biochem.Biophys.Acta.996. 142-145 (1989)
[Publications] Ohta,K.: "Interspecies homology of cytochrome P-450 cross-reactive with anti-rat P-448-II antibodies in liver microsomes from dogs,monkeys and humans." Mutation Research. 226. 163-167 (1989)
[Publications] Kitada,M.: "Immunochemical studies for the presence of P-450 HFLa,a form of cytochrome P-450 in human fetal livers in human hepatocellular carcinoma cells." J.Pharmacobio-Dyn.12. 341-344 (1989)
[Publications] Komori,M.: "Evidence for expression of a limited number of form(s)of cytochrome P-450 in human fetal livers." Archs.Biochem.Biophys.272. 219-225 (1989)
[Publications] Miura,T.: "Decrease in a constitutive form of cytochrome P-450 by macrrolide antibiotics." J.Antimicrobial Chemotherapy. 24. 551-559 (1989)
[Publications] Kitada,M.: "Mutagenic activation of aflatoxin B1 by P-450 HFLa in human fetal livers." Mutation Research. 227. 53-58 (1989)
[Publications] Sano,K.: "Distributional variation of P-450 immunoreactive hepatocytes in human liver disorders." Human Pathology. 20. 1015-1020 (1989)
[Publications] Ohta,K.: "Interspecies homology of cytochrome P-450:Purification and toxicological significance of a high spin form of cytochrome P-450(P-450-D2)from liver microsomes of polychlorinated biphenyl(PCB)-treated beagle dogs." J.Biopharm.Sci.(1989)
[Publications] Komori,M.: "Fetus-specific expression of a form of cytochrome P-450 in human livers." Biochemistry. (1990)
[Publications] Sogawa,K.: "Repression of cytochrome P-450c gene expression by cotransfection with adenovirus Ela DNA." Eur.J.Biochem.181. 539-544 (1989)
[Publications] Yanagida,A.: "A novel cis-acting DNA element required for a high level of inducible expression of the P-450c gene." Mol.Cell.Biol.(1990)
[Publications] Imaoka,S.: "ω-and(ω-1)-hydroxylation of lauric acid and arachidonic acid by rat renal cytochrome P-450." Biochem.Internat.18. 731-740 (1989)
[Publications] Imaoka,S.: "Expression of four phenobarbital-inducible cytochrome P-450s in liver,kidney,and lung of rats." J.Biochem.105. 939-945 (1989)
[Publications] Kitada,M.: "Form-specific degradation of cytochrome P-450 by lipid peroxidation in rat liver microsomes." Res.Commun.Chem.Pathol.Pharmacol.63. 175-187 (1989)
[Publications] Kikuta,Y.: "Purification and characterization of hepatic microsomal prostaglandin ω-hydroxylase cytochrome P-450 from pregnant rabbits." J.Biochem.106. 468-473 (1989)
[Publications] Yamazoe,Y.: "Suppression of hepatic levels of an ethanol-inducible P-450DM/j by growth hormone:relationship between the increased level of P-450DM/j and depletion of growth hormone in diabetes." Mol.Pharmacol.36. 716-722 (1989)
[Publications] Oda,Y.: "Metabolism of lidocaine by purified rat liver microsomal cytochrome P-450 isozymes." Biochem.Pharmacol.38. 4439-4444 (1989)
[Publications] Nemoto,N.: "Proline-dependent expression of aryl hydrocarbon hydroxylase in C57BL/6 mouse hepatocytes in primary culture." Cancer Res.49. 5863-5869 (1989)
[Publications] Fujita,S.: "Evaluation of the involvement of a male specific cytochrome P-450 isozyme in senescence-associated decline of hepatic drug metabolism in male rats." Biochem.Pharmacol.38. 3925-3931 (1989)
[Publications] Chiba,M.: "Kinetic properties of the metabolism of imipramine and desipramine in isolated rat hepatocytes." Biochem.Pharmacol.39. 367-372 (1990)
[Publications] Chiba,M.: "Pharmacokinetic correlation between in vitro hepatic microsomal enzyme and in vivo disposition of imipramine and desipramine in rats." J.Pharm.Sci.79. (1990)
[Publications] Fujita,S.: "Alteration of plasma sex hormone levels associated with old age and its effect on hepatic drug metabolism in rats." J.Pharmacol.Exp.Ther.(1990)
[Publications] Fujita,S.: "Age-associated alterations in diazepam metabolizing enzyme activities in male and female rats." Drug.Metabol.Dispos.(1990)
[Publications] Satoh,K.: "Transient induction of single GST-P positive hepatocytes by DEN." Carcinogenesis. 10. 2107-2111 (1989)
[Publications] Tsuchida,S.: "Elevation of the placental glutathione S-transferase form(GST-π)in tumor tissues and the levels in sera of patients with cancer." Cancer Res.49. 5225-5229 (1989)
[Publications] Tamai,K.: "Specific inactivation of glutathione S-transferases in class Pi by SH-modifiers." Biochem.Biophys.Res.Commun.(1990)
[Publications] Sakai,M.: "Structure and expression of the rat c-jun messenger RNA:Tissue distribution and increase during chemical hepatocarcinogenesis." Cancer Res.49. 5633-5637 (1989)
[Publications] Hiratsuka,A.: "A new class of rat glutathione S-transferase Yrs-Yrs inactivating reactive sulfate esters as metabolites of carcinogenic arylmethanols." J.Biol.Chem.(1990)
[Publications] Tsuchida,S.: "Purification and characterization of glutathione transferases with an activity toward nitroglycerin from human aorta and heart." J.Biol.Chem.(1990)
[Publications] Yamazoe,Y.: "Enzymatic acetylation and sulfation of N-hydroxyarylamines in bacteria and rat livers." Carcinogenesis. 10. 1675-1679 (1989)
[Publications] Yasumori,T.: "Expression of a human P-450IIC gene in yeast cells using galactose-inducible expression system." Mol.Pharmacol.35. 443-449 (1989)
[Publications] Watanabe,M.: "Cytochrome P-450:Biochemistry and Biophysics.ed.by Schuster,I." Taylor and Francis,London., 536-539 (1989)
[Publications] Sato,K.: "Glutathione Centennial:Molecular Perspectives and Clinical Implications.eds.by Sakamoto,Y.,Higashi,T.,Taniguchi,N.and Meister,A." Academic Press Inc.,New York., 259-270 (1989)
[Publications] Sato,K.: "Glutathione S-transferases and drug resistance.eds.by Hayes,J.,Hayes,P.C.,Mantle,T.J.and Pickett,C." Taylor and Francis,London., (1990)
[Publications] Kato,R.: "Xenobiotic Metabolism and Disposition.eds.by Kato,R.,Estabrook,R.W.and Cayen,M.N." Taylor and Francis,London., 383-391 (1989)

1989 Fiscal Year Annual Research Report

チトクロームPー450を中心とした薬物代謝酵素遺伝子発現と化学発癌

Principal Investigator

渡辺 民朗 東北大学, 抗酸菌病研究所, 教授 (40006101)

Research Products

[Publications] Ohmachi,T.: "Purification and characterization of cytochrome P-450 from liver microsomes of 3-methylcholanthrene-treated crab-eating monkeys." J.Biochem.105. 307-311 (1989)

[Publications] Watanabe,M.: "Role of cytochrome P-450 in chemical toxicity and carcinogenesis." J.Toxicol.Pathol.2. 241-251 (1989)

[Publications] Kikuchi,H.: "Complementary DNA sequence of 3-methylcholanthrene-inducible P-450 from the rat lung." Tohoku J.Exp.Med.(1990)

[Publications] Komori,M.: "Molecular cloning and sequence analysis of cDNA containing the entire coding region for human fetal liver cytochrome P-450." J.Biochem.105. 161-163 (1989)

[Publications] Ohta,K.: "Purification of cytochrome P-450 from polychlorinated biphenyl-treated crab eating monkeys:High homology to a form of human cytochrome P-450." Biochem.Biophys.Acta.996. 142-145 (1989)

[Publications] Ohta,K.: "Interspecies homology of cytochrome P-450 cross-reactive with anti-rat P-448-II antibodies in liver microsomes from dogs,monkeys and humans." Mutation Research. 226. 163-167 (1989)

[Publications] Kitada,M.: "Immunochemical studies for the presence of P-450 HFLa,a form of cytochrome P-450 in human fetal livers in human hepatocellular carcinoma cells." J.Pharmacobio-Dyn.12. 341-344 (1989)

[Publications] Komori,M.: "Evidence for expression of a limited number of form(s)of cytochrome P-450 in human fetal livers." Archs.Biochem.Biophys.272. 219-225 (1989)

[Publications] Miura,T.: "Decrease in a constitutive form of cytochrome P-450 by macrrolide antibiotics." J.Antimicrobial Chemotherapy. 24. 551-559 (1989)

[Publications] Kitada,M.: "Mutagenic activation of aflatoxin B1 by P-450 HFLa in human fetal livers." Mutation Research. 227. 53-58 (1989)

[Publications] Sano,K.: "Distributional variation of P-450 immunoreactive hepatocytes in human liver disorders." Human Pathology. 20. 1015-1020 (1989)

[Publications] Ohta,K.: "Interspecies homology of cytochrome P-450:Purification and toxicological significance of a high spin form of cytochrome P-450(P-450-D2)from liver microsomes of polychlorinated biphenyl(PCB)-treated beagle dogs." J.Biopharm.Sci.(1989)

[Publications] Komori,M.: "Fetus-specific expression of a form of cytochrome P-450 in human livers." Biochemistry. (1990)

[Publications] Sogawa,K.: "Repression of cytochrome P-450c gene expression by cotransfection with adenovirus Ela DNA." Eur.J.Biochem.181. 539-544 (1989)

[Publications] Yanagida,A.: "A novel cis-acting DNA element required for a high level of inducible expression of the P-450c gene." Mol.Cell.Biol.(1990)

[Publications] Imaoka,S.: "ω-and(ω-1)-hydroxylation of lauric acid and arachidonic acid by rat renal cytochrome P-450." Biochem.Internat.18. 731-740 (1989)

[Publications] Imaoka,S.: "Expression of four phenobarbital-inducible cytochrome P-450s in liver,kidney,and lung of rats." J.Biochem.105. 939-945 (1989)

[Publications] Kitada,M.: "Form-specific degradation of cytochrome P-450 by lipid peroxidation in rat liver microsomes." Res.Commun.Chem.Pathol.Pharmacol.63. 175-187 (1989)

[Publications] Kikuta,Y.: "Purification and characterization of hepatic microsomal prostaglandin ω-hydroxylase cytochrome P-450 from pregnant rabbits." J.Biochem.106. 468-473 (1989)

[Publications] Yamazoe,Y.: "Suppression of hepatic levels of an ethanol-inducible P-450DM/j by growth hormone:relationship between the increased level of P-450DM/j and depletion of growth hormone in diabetes." Mol.Pharmacol.36. 716-722 (1989)

[Publications] Oda,Y.: "Metabolism of lidocaine by purified rat liver microsomal cytochrome P-450 isozymes." Biochem.Pharmacol.38. 4439-4444 (1989)

[Publications] Nemoto,N.: "Proline-dependent expression of aryl hydrocarbon hydroxylase in C57BL/6 mouse hepatocytes in primary culture." Cancer Res.49. 5863-5869 (1989)

[Publications] Fujita,S.: "Evaluation of the involvement of a male specific cytochrome P-450 isozyme in senescence-associated decline of hepatic drug metabolism in male rats." Biochem.Pharmacol.38. 3925-3931 (1989)

[Publications] Chiba,M.: "Kinetic properties of the metabolism of imipramine and desipramine in isolated rat hepatocytes." Biochem.Pharmacol.39. 367-372 (1990)

[Publications] Chiba,M.: "Pharmacokinetic correlation between in vitro hepatic microsomal enzyme and in vivo disposition of imipramine and desipramine in rats." J.Pharm.Sci.79. (1990)

[Publications] Fujita,S.: "Alteration of plasma sex hormone levels associated with old age and its effect on hepatic drug metabolism in rats." J.Pharmacol.Exp.Ther.(1990)

[Publications] Fujita,S.: "Age-associated alterations in diazepam metabolizing enzyme activities in male and female rats." Drug.Metabol.Dispos.(1990)

[Publications] Satoh,K.: "Transient induction of single GST-P positive hepatocytes by DEN." Carcinogenesis. 10. 2107-2111 (1989)

[Publications] Tsuchida,S.: "Elevation of the placental glutathione S-transferase form(GST-π)in tumor tissues and the levels in sera of patients with cancer." Cancer Res.49. 5225-5229 (1989)

[Publications] Tamai,K.: "Specific inactivation of glutathione S-transferases in class Pi by SH-modifiers." Biochem.Biophys.Res.Commun.(1990)

[Publications] Sakai,M.: "Structure and expression of the rat c-jun messenger RNA:Tissue distribution and increase during chemical hepatocarcinogenesis." Cancer Res.49. 5633-5637 (1989)

[Publications] Hiratsuka,A.: "A new class of rat glutathione S-transferase Yrs-Yrs inactivating reactive sulfate esters as metabolites of carcinogenic arylmethanols." J.Biol.Chem.(1990)

[Publications] Tsuchida,S.: "Purification and characterization of glutathione transferases with an activity toward nitroglycerin from human aorta and heart." J.Biol.Chem.(1990)

[Publications] Yamazoe,Y.: "Enzymatic acetylation and sulfation of N-hydroxyarylamines in bacteria and rat livers." Carcinogenesis. 10. 1675-1679 (1989)

[Publications] Yasumori,T.: "Expression of a human P-450IIC gene in yeast cells using galactose-inducible expression system." Mol.Pharmacol.35. 443-449 (1989)

[Publications] Watanabe,M.: "Cytochrome P-450:Biochemistry and Biophysics.ed.by Schuster,I." Taylor and Francis,London., 536-539 (1989)

[Publications] Sato,K.: "Glutathione Centennial:Molecular Perspectives and Clinical Implications.eds.by Sakamoto,Y.,Higashi,T.,Taniguchi,N.and Meister,A." Academic Press Inc.,New York., 259-270 (1989)

[Publications] Sato,K.: "Glutathione S-transferases and drug resistance.eds.by Hayes,J.,Hayes,P.C.,Mantle,T.J.and Pickett,C." Taylor and Francis,London., (1990)

[Publications] Kato,R.: "Xenobiotic Metabolism and Disposition.eds.by Kato,R.,Estabrook,R.W.and Cayen,M.N." Taylor and Francis,London., 383-391 (1989)

渡辺民朗東北大学, 抗酸菌病研究所, 教授 (40006101)